2-benziminazoyl-amino pyrimidines



Patented Feb. l, 1949 UNITED STATES A PATENT j o ncZ-BENZIIMINAZOYL-AMINO PYRIMIDINES Frederick Robert Basford, FrancisHenry Swinden Curd, and Francis Leslie Rose, Blackley, Manchester,England, assignors to Imperial Chemical Industries Limited, acorporation of Great Britain No Drawing. Application October 4, 1946,Serial No. 7 01,092. In Great Britain October 9, 1945 I 9 Claims.

This invention relates to the manufactureof new pyrimidine compoundswhich are useful as chemotherapeutic agents and particularly asparasiticidal agents, especially against the parasites that causemalaria. I

The said new compounds are pyrimidine derivatives of the formula.

wherein X- and Y, which are not necessarily alike, each representhydrogen or a hydrocarbon radical or X and Y together represent adivalent aliphatic hydrocarbon radical which forms with the and G-carbonatoms an alicyclic ring; wherein the benz ring of the benziminazolylgroup may be 7 unsubstituted or may bear one or more nonacidicsubstituents such, for example, as hydrocarbon radicals (whichthemselves may optionally bear substituents and which may be at tacheclto the benz radical directly or indirectly as, for instanceythrough anoxygen, sulphur or nitrogen atom or may be fused thereto as in the maybe used in. the form of a salt, such as the case of, a naphthiminazolylradical), halogen I atoms or nitro or cyano groups; wherein R" ishydrogen or an alkyl or simply substituted alkyl, group, for example analkoxyalkyl or dittlk'ylaminoalkyl group; wherein A is'a linking groupwhich is aliphatic or alicyclic or aliphatic-carbocyclic and may besubstituted, for example, by hydror 'c"'rb0nradicals, hydroxy 'or alkoxygroups or dialkylaminoalkyl groups and where A or part of A is analiphatic chain it may be interrupted by oxygen,sulphur or nitrogenatoms; and wherein NRR' is a strongly basic amino or substituted aminogroup such as alkylamino 'or dialkylamino or piperidino or otherstrongly basic nitrogencontaining heterocyclic group. We make the saidcompounds NRR' with an appropriate 2-(benziminazolyl- (2')-amino)-pyrimidine bearing in the 5- and,

G-positibns the groups X and Y respectively and in the Jr-position alabile group such as a halogen. atom or, a hydrocarbon radical which isattached bya process corn-f prising the interaction of a diamineNHR"--A--' hydrochloride or acetate. .Also if desired, the reaction maybe carried out in the presence of an acid-binding agent such as sodiumhydroxide.

The reagents are conveniently, but not necessarily, used inapproximately stoichiometric proportions. If desired, a large excess ofthe amine may be used so that it functions as a solvent or diluent.

. A further feature of the invention'is a modified 7 process wherein thebasic substituent N "-A- NRR' is introduced by stages. Thus thebenziminazolylamino-pyrimidine compound carrying a labile group in the4-position is brought into reaction with an amino-compound of the formNHR"A-B, where A represents either the whole or a part of the linkinggroup A defined above and where B stands for a reactive group which isthen converted by known methodsi'nto' the group NRR or into a groupA"--NRR' such that A and A" together constitute the linking group A. Forexample, the group B may be a:.

hydroxy group or a derivative thereof which is, or is readilyconvertible to, 'a reactive ester thereof, such as a halide, this thenbeing brought into reactionwith'an amine NHRR' or an amino ormercapto-substituted amine HO -A--NRR" or H S'A "'-NRR (or an alkalimetal derivative of such a hydroxy or mercapto compound) such, thatANI-I-A' A'--OA' or A--S" constitutes the linking group A previously;mentioned. Another alternative is to bring the labile group in the4-position of the benziminazolylaminopyrimidine compound into reactionwith an acylated diamine NHR;A

- NHAc and'thento hydrolyse off the acyl group. Further, if desired, thefree amino group so generated may be modified, as by alkylation,conversion to'a heterocyclic group such as piperidino or by bringing itinto reaction with a halogenosubstituted amine Hal--ANRR" such that bymeans of an ether or thioether linkage, for

example, an alkoxy, aryloxy'or alkylmercapto' group.

The reaction is conveniently brought about by heating the reagentstogether, optionally in presence of asolvent ordiluent; If desired, thebenziminazolylaminopyrimidine orxthe diamine A'-NHA' constitutes thelinking group A.

The 4-halogeno-2-benziminazolylaminopyrimidine compounds used asstarting materials may l conveniently be made from the corresponding 4-hydroxy-2 ben'ziminazolylaminopyrimidine com- 2 parts of thehydrochloride of 2-(benziminazolyl (2) -amino)-4-chloro-6methylpyrimidine, 4 parts of B-diethylaminoethylamine and0.01 part of potassium iodide are stirred and heated together at ISO-160C. for 6 hours. The melt is then cooled and extracted with dilutehydrochloric acid. The extract is clarified with charcoal and then madealkaline with ammonia. A white solid is precipitated. This is crude 2-(benziminazolyl- (2') -amino) 443- diethylaminoethylamino-GmethyIpyrimidine, whose structure may be represented by the followingformula- It is filtered off and purified by recrystallisation frombenzene when it has M. P. 198-200 C.

Working in a similar manner but starting from other appropriate4-halogeno-2-benziminazolylaminopyrimidines and appropriate diamines,the following further compounds can be made; the table indicates theconstitution of the compounds and their respective melting points.

S-diethylaminopropylamine and 0.03 part of potassium iodide are heatedtogether at l-165 C. for 6 hours. The mixture is then dissolved indilute acetic acid, the solution is filtered and the filtrate is made.alkaline with sodium hydroxide. It is then filtered and the solid iswashed with Water and dried. It crystallises from a mixture of benzeneand ligroin and has M. P. 183-184" C.

Example 14 4 parts of. 4echloro-2-benziminazolyl-(2)-amino--'6-methylpyrimidine, 8 parts of 'y-dibutylamino-propylami neand0.04 part of potassium iodide are heated in an oil bath at USO- C. for 8hours. The resulting reaction mixture is dissolved in a mixture of 20parts of water and 10 parts of hydrochloric acid, the solution isfiltered and the filtrate is made alkaline with sodium hydroxide. Theprecipitated product is filtered off, washed with water, dried andcrystallised from a mixture of benzene and ligroin. P. 1"58'C.

In the claims belowfthe expression acidic substituents refers toradicals commonly recognized as ionizable, salt-forming, a cid radicals;as typified by carboxy and sulfo radicals.

We claim:

1. A compound of the pyrimidine series characterized by carrying abenziminazolyl-amino radical in the 2-position, said benziminazolylaminoradical being free of acidic substituents; and carrying the radical of'adiaminetin the 4- position, said diamine radical having the form-NH-ANR.R.,'wherein NRR .is a strongly basic radical selected from thegroupconsisting of primary, secondary and tertiary amine radicals andheterocyclicnitrogenous base radicals, while Ex. No. Constitution ofCompound gg fi2-(5'-(6)-chlorobenziminazoly1-(2)-amino)-4-5-diethylaminoethylamino-fi-methylpyriniidine204-20 2-(5(6)-chlorobenziminazolyl-(2)-amino)-4--diethylaminopropylamino-fi-methylpyrm ld ne i c 1932-(5-(6)-chlorobenzimi nazolyl-(2)-amino)-4---dimethylaminopropylamino-fi-methylpyrim dme 196-1972-(5-(6)-chlorobenziminazolyl-(2)-amino)-4-- -djbutylaminopropylammofimethylpyrimidine 166-167 2-(5-(6)-chlorobenziminazolyl-(2')-amino)4--(Nmethyl-Nisopropylammo)-propylammo-fi-methylpyrimidme; 203

N=COHa Cl- C-NH-(f ("3H N; bk-C-NHCH.CH2.CHr-NCH:

I zH'I-(iSO).

(The (ll-atom is located in one of the positions 5', 6')

72-(5-(6)-chlorobenziminazolyl-(2)-amino)-4-B-piperidinoethylamino-dmethylpygimifline223 8 2-(5-(6)-chlorobenziminazolyl-(2)-a.mino)-4-'y-(8-diethylaminoethoxy)-pr0pylammo-fi-methylpynmidme, 162

EE Cl CNH%[3 ("3H NC-NH-CH CHi.CH -Q CliizClirN 0.2 35);

92-(546)-mcthoxybenziminazolyl-(2!)-amino)-4-'y-diethylaminopropylamino-S-methylpyrimidinee 164456 10 2-(5-(6)-methoxybenziminazolyl-(2)-amino)4--dibutylaminopropylamino-fi-methylpyrimidine 158-159 112-(5(6)-methylbenziminazo1yl-(2)amino)-4-B-diethy1aminoethylamino-G=metl1y1pyrimidinc 210 12Z-(naphtho-l22":4:5-i.minazolyl-(2)-amino)-4-fi-diethylaminoethylamino-fi-methylpyrimidine,226

N N=C-CH:

C-NH-(fl) "H 4 N-C-NHC Hz.CH2--N (C2115) Ezvample 13 v 3 parts of4-chloro-2(5'-methylbenziminazolyl- 2'-'amino) -'6-methylpyrimidine and:52 parts -of A isua :linksing radicaluselectedfr'om the group,

consisting. of aliphatic, alicyclic .and. aliphaticcarbocyclicbivalenttradicals.

2. As new compounds, the pyrimidine derivatives of the formula- N=X q-tld-Y d--NH-A-NRR' wherein Q stands for a benziminazolyl-amino group whichis free of acidic substituents, A is a linking radical selected from thegroup'consisting of aliphatic, alicyclic and aliphatic-carbocyclicbivalent radicals, NRR' is a strongly basic radical selected from thegroup consisting of primary, secondary and tertiary amine radicals andheterocyclic nitrogenous base radicals, while X and Y represent membersselected from the group consisting of hydrogen and hydrocarbon radicals.

3. As new compounds, the pyrimidine derivatives of the formula- Q-(k(E-Y N -N HANRR' wherein Q stands for a benziminazolyl-amino group whichis free of acidic substituents, A is an aliphatic link joining theN-atom of the NH group to the N-atom of the NRR' group'and interposingtherebetween at least two carbon atoms, NRR' is a dialkylamino group,while X and Y represent members selected from the group consisting ofhydrogen and hydrocarbon radicals.

4. As new compounds, pyrimidine derivatives of the formula- N=O-X O NH Et Y I L- NHANRR' aminoalkylamino pyrimidines bearing in the 2- positiona 2-benziminazoly1-amino radical.

6. 2-[6-chlorobenziminazolyl-(2') aminol-4-'y-dimethyl-aminopropylamino-B-methylpyrimi dine.

7. 2- [6'-chlorobenziminazolyl- (2') -amino] -4fl-diethylaminoethylamino-6-methylpyrimidine.

8. 2- [6'-chlorobenziminazolyl- (2) -amino]-4p-piperidi'no-ethylamino-6-methylpyrimidine.

9. A process for the manufacture of compounds as defined in claim 1,which comprises reacting I a 4-halogeno pyrimidine compound bearing inthe 2-position a 2-benziminazolyl-amino radical, with a diamine of theformula NH2A-NRR, wherein NRR is a strongly basic radical selected fromthe group consisting of primary, secondary and tertiary amine radicalsand heterocyclic nitrogenous base radicals, while A is a linking radicalselected from the group consisting of aliphatic, alicyclic andaliphatic-carbocyclic bivalent radicals.

FREDERICK ROBERT BASFORD. FRANCIS HENRY SWINDEN CURD. FRANCIS LESLIEROSE.

No references cited

